Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

Schwartz, Daniella M.; Kanno, Yuka; Villarino, Alejandro V.; Ward, Michael M.; Gadina, Massimo; O’Shea, John J.

doi:10.1038/nrd.2017.267

Cited by 285 publications

(116 citation statements)

References 188 publications

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“…In myeloproliferative neoplasms the JAK-STAT signaling pathway can be inhibited with the JAK1/JAK2 inhibitor ruxolitinib and in rheumatoid arthritis with less selective JAK inhibitors such as tofacitinib and baricitinib [31]. Several other pharmacological compounds affecting the JAK-STAT pathway are currently investigated in clinical trials [31]. We hypothesized that drugs investigated for other indications might induce differential sensitivity in cancer cell lines with active JAK-STAT signaling.…”

Section: Novel Potential Inhibitors Of Stat3 Activationmentioning

confidence: 99%

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

Andersson

Brück

Braun

et al. 2020

Cancers

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Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK + ALCL, 38% of ALK − ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK -ALCL (15%). Concurrent mutations were found in all subgroups except ALK + ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30 + phenotype representing primarily ALK − ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL.Cancers 2020, 12, 702 2 of 17 diagnoses [1]. The most prevalent PTLCs are PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-negative (ALK − ALCL), and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK + ALCL) [2,3].Despite generally favorable response rates to chemotherapy, remissions are often not durable, and as such the natural history of PTCL is characterized by relapses and refractory disease. For this reason, upfront hematopoietic stem cell transplantation (HSCT) is often recommended in first remission for patients who are fit and have chemo-sensitive disease [4]. For patients who are not suitable for transplantation, chances of long-term disease control are very limited, with an average progression-free survival (PFS) of 5.5 months [5]. In this setting, optimal therapeutic approaches remain undefined representing an unmet clinical need.Recent advances in the molecular and genetic characterization of PTCL have helped to delineate differences and similarities between the various subtypes [6]. Several recurrent mutations have been identified in small subsets of patients potentially enabling more accurate disease classification and guide treatment decisions. In AITL, the three most commonly identified genetic lesions occur in the Tet methylcytosine dioxygenase 2 gene (TET2), the Ras homolog gene family, member A (RHOA), and the isocitrate dehydrogenase 2 gene (IDH2). Besides AITL, TET2 mutations can be seen with a high frequency also in PTCL-NOS with a T follicular helper cell phenotype [7]. RHOA, a small GTPase participating i...

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Section: Novel Potential Inhibitors Of Stat3 Activationmentioning

confidence: 99%

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

Andersson

Brück

Braun

et al. 2020

Cancers

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“…Given the apparent importance of STAT3 in pathogenic Th17 cell development, it is no surprise that therapeutics targeting upstream STAT3 activation, via cytokines and JAK inhibitors, are being investigated as treatments for autoimmune disease (Schwartz et al, 2017). The importance of STAT3 has mostly been studied in systems in which STAT3 was deleted before initiation of the Th17 response, such as in mice with constitutive STAT3 deletion in T cells or humans with genetic mutations present from birth.…”

Section: Introductionmentioning

confidence: 99%

Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

Poholek

Raphael

et al. 2020

Journal of Experimental Medicine

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The STAT3 signaling pathway is required for early Th17 cell development, and therapies targeting this pathway are used for autoimmune disease. However, the role of STAT3 in maintaining inflammatory effector Th17 cell function has been unexplored. Th17ΔSTAT3 mice, which delete STAT3 in effector Th17 cells, were resistant to experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Th17 cell numbers declined after STAT3 deletion, corresponding to reduced cell cycle. Th17ΔSTAT3 cells had increased IL-6–mediated phosphorylation of STAT1, known to have antiproliferative functions. Th17ΔSTAT3 cells also had reduced mitochondrial membrane potential, which can regulate intracellular Ca2+. Accordingly, Th17ΔSTAT3 cells had reduced production of proinflammatory cytokines when stimulated with myelin antigen but normal production of cytokines when TCR-induced Ca2+ flux was bypassed with ionomycin. Thus, early transcriptional roles of STAT3 in developing Th17 cells are later complimented by noncanonical STAT3 functions that sustain pathogenic Th17 cell proliferation and cytokine production.

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“…Постоянно расширяющийся перечень ГИБП включает моноклональные антитела (мАТ) к различным детерминантам иммунокомпетентных клеток или цитокинам и гибридные белковые молекулы, ингибирующие активность цитокинов или взаимодействие Т-и В-лимфоцитов [6,[10][11][12][13]. Разработан новый класс таргетных препаратов, представляющих собой химически синтезированные малые молекулы, ингибирующие тирозинкиназы, прежде всего Janus-киназы (JAK), которые через соответствующие трансмембранные рецепторы передают сигналы от цитокинов к ядерным генам-мишеням [6,[14][15][16] недостаточной эффективностью или переносимостью) на препарат с другой направленностью действия. Вторичная неэффективность (ускользание терапевтического эффекта) ГИБП может быть связана с так называемой иммуногенностью (образованием антител к мАТ) [18], что зависит от молекулярной структуры препарата и его посттрансляционных модификаций в процессе производства, а также схемы лечения, индивидуальных особенностей пациента.…”

Section: The Development Of Rheumatology At the Stage Of Formation Ofunclassified

The development of rheumatology at the stage of formation of a new technological paradigm

Бекетова¹

2019

Naučno-praktičeskaâ revmatologiâ

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Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

Cited by 285 publications

References 188 publications

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

The development of rheumatology at the stage of formation of a new technological paradigm

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